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United States Patent |
5,523,423
|
Murthy
,   et al.
|
June 4, 1996
|
Form of form 1 Ranitidine
Abstract
Process for the production of an improved form of Form 1 Ranitidine
Hydrochloride having improved filtration and drying characteristics, said
process comprising in a substantially anhydrous hydroxylic solvent,
comprising at least one alkanol solvent having 3-4 carbon atoms, adding
anhydrous hydrogen chloride gas to Ranitidine free base wherein said
substantially anhydrous hydroxylic solvent has the characteristics that it
solubilizes the Ranitidine free base and hydrogen chloride gas, and
subsequently recovering the improved form of Form 1 Ranitidine
Hydrochloride.
Inventors:
|
Murthy; Keshava (Brantford, CA);
Radatus; Bruno K. (Brantford, CA);
Swidhu; Kanwarpal S. (Brantford, CA)
|
Assignee:
|
ACIC (Canada) Inc. (Brantford, CA)
|
Appl. No.:
|
458253 |
Filed:
|
June 2, 1995 |
Current U.S. Class: |
549/495 |
Intern'l Class: |
C07D 307/52 |
Field of Search: |
549/491,495
|
References Cited
U.S. Patent Documents
4128658 | Dec., 1978 | Price et al. | 549/495.
|
4521431 | Jun., 1985 | Crookes | 549/495.
|
4672133 | Jun., 1987 | Crookes | 549/495.
|
Primary Examiner: Ivy; C. Warren
Assistant Examiner: Owens; Amelia
Attorney, Agent or Firm: Hughes; Ivor M., Hughes; Neil H., Sarkis; Marcelo K.
Parent Case Text
This application is a divisional of application Ser. No. 08/418,401, filed
Apr. 7, 1995 (status: Pending).
Claims
The embodiments of the invention in which an exclusive property or
privilege is claimed are as follows:
1. An improved form of Form 1 Ranitidine Hydrochloride having improved
drying and filtration characteristics and having:
(i) a bulk density of not less than about 0.23 gm/ml; and
(ii) a tap density of not less than about 0.28 gm/ml.
2. An improved form of Form 1 Ranitidine Hydrochloride having improved
drying and filtration characteristics and having:
(i) a bulk density of not less than about 0.23 gm/ml; and
(ii) a tap density of not less than about 0.28 gm/ml when produced
according to a process selected from the group of processes consisting of
the following processes:
(i) process for the production of an improved form of Form 1 Ranitidine
Hydrochloride having improved filtration and drying characteristics, said
process comprising in a substantially anhydrous hydroxylic solvent,
comprising at least one alkanol solvent having 3-4 carbon atoms, adding
anhydrous hydrogen chloride gas to Ranitidine free base wherein said
substantially anhydrous hydroxylic solvent has the characteristics that it
solubilizes the Ranitidine free base and hydrogen chloride gas, and
subsequently recovering the improved form of Form 1 Ranitidine
Hydrochloride;
(ii) process for the production of a improved form of Form 1 Ranitidine
Hydrochloride having improved filtration and drying characteristics, said
process comprising adding Ranitidine Hydrochloride to a substantially
anhydrous hydroxylic solvent comprising at least one alkanol having 3-4
carbon atoms, which has the characteristics that it dissolves Ranitidine
Hydrochloride and subsequently recovering the improved form of Form 1
Ranitidine Hydrochloride;
(iii) the process of sub-paragraph (i) or (ii) wherein the solution is in
the order of between about 40.degree. C. to about 55.degree. C. when the
improved form of Form 1 Ranitidine Hydrochloride is crystallized from the
solution;
(iv) the process of sub-paragraph (i) wherein the anhydrous hydrogen
chloride gas is introduced to the solution of Ranitidine free base as an
anhydrous solution;
(v) the process of sub-paragraph (i), (ii), (iii), or (iv) wherein the
hydroxylic solvent is a lower alkanol having 3 to 4 carbon atoms; and,
(vi) the process of sub-paragraph (i), (ii), (iii), (iv), or (v) wherein
the solvent comprises isopropanol.
3. An improved form of Form 1 Ranitidine Hydrochloride made according to
the process of sub-paragraph (i) of claim 2.
4. An improved form of Form 1 Ranitidine Hydrochloride made according to
the process of sub-paragraph (ii) of claim 2.
5. An improved form of Form 1 Ranitidine Hydrochloride made according to
the process of sub-paragraph (iii) of claim 2.
6. An improved form of Form 1 Ranitidine Hydrochloride made according to
the process of sub-paragraph (iv) of claim 2.
7. An improved form of Form 1 Ranitidine Hydrochloride made according to
the process of sub-paragraph (v) of claim 2.
8. An improved form of Form 1 Ranitidine Hydrochloride made according to
the process of sub-paragraph (vi) of claim 2.
Description
FIELD OF INVENTION
This invention relates to an improved form of Form 1 Ranitidine
Hydrochloride and processes for the manufacture thereof.
BACKGROUND OF THE INVENTION
Canadian Letters Patent 1,099,268 (corresponding to U.S. Pat. No. 4,128,658
and U.K. Patent 1565966) teaches the medicine Ranitidine and salts thereof
(including the hydrochloride salt) and processes for the manufacture
thereof.
Canadian Letters Patent 1,202,638 (corresponding to U.S. Pat. Nos.
4,521,431 and 4,672,133) purports to teach a specific new form of
Ranitidine Hydrochloride which form the Inventor, Mr. Derek L. Crookes,
termed "Form 2" to purportedly distinguish the purportedly new form from
the purported forms taught in the original patents (Canadian Letters
Patent 1,099,268, U.S. Pat. No. 4,128,658, U.K. Patent 1565966 and all
corresponding patents and which form taught by these patents the Inventor
identified as Form 1 forms of Ranitidine Hydrochloride).
Mr. Crookes asserted in the later patents (Canadian Letters Patent
1,202,638 and U.S. Pat. Nos. 4,521,431 and 4,672,133) that the procedures
for producing (crystallizing) Ranitidine Hydrochloride in accordance with
the teachings of said U.K. Patent 1565966 (and thus under corresponding
U.S. Pat. No. 4,128,658 and Canadian Letters Patent 1,099,268)
does not have the desirable features of a manufacturing process described
above and Form 1 of the hydrochloride salt has unsuitable filtration and
drying characteristics
(page 2, line 35-page 3, line 1 of Canadian Letters Patent 1,202,638)
The only method by which Mr. Derek L. Crookes could overcome the
deficiencies and limitations of the purported Form 1 Ranitidine
Hydrochloride was to develop a purported new form of Ranitidine
Hydrochloride (identified as Form 2 to distinguish the purported new form
from the old form (termed Form 1)) and which purported Form 2 Ranitidine
Hydrochloride overcame the deficiencies and limitations of the purported
Form 1 Ranitidine Hydrochloride.
It is therefore an object of this invention to provide an improved form of
Form 1 Ranitidine Hydrochloride which overcomes the previously described
deficiencies and limitations of previous forms of Form 1 Ranitidine
Hydrochloride and to provide Form 1 Ranitidine Hydrochloride which has
better filtration and drying characteristics.
It is a further object of this invention to provide processes for the
manufacture of the improved form of Form 1 Ranitidine Hydrochloride which
processes provide the improved form of Form 1 Ranitidine Hydrochloride
consistently and in goods yields.
Further and other objects of the invention will be realized by those
persons skilled in the art from the following Summary of the Invention and
Detailed Description of Embodiments thereof.
In this regard should other salts of Ranitidine in a form which has
unsuitable filtration and drying characteristics be developed, it is a
further object of this invention to provide processes which can be used to
produce a better form of the salt of Ranitidine which has acceptable
filtration and drying characteristics.
SUMMARY OF THE INVENTION
According to one aspect of the invention, a new process for consistently
producing Form 1 Ranitidine Hydrochloride having improved filtration and
drying characteristics is provided, the said process comprising adding a
solution of anhydrous hydrogen chloride gas in substantially anhydrous
isopropanol to a solution of Ranitidine Free Base in substantially
anhydrous isopropanol preferably containing seeds of Form 1 Ranitidine
Hydrochloride (for example the Ranitidine Hydrochloride termed Form 1 by
Glaxo Group Limited produced under Canadian Letters Patent 1,099,268) at
for example temperatures in the order of between about 40.degree. C. to
about 55.degree. C. and subsequently recovering (as by crystallization
through precipitation) the improved Form 1 Ranitidine Hydrochloride as for
example by filtration and/or centrifuging. The isopropanol is expected to
be anhydrous; however small amounts of water (for example less than about
2% preferably less than about 1% and more preferably less than about 0.5%)
are not deleterious to the processes.
All or some of the isopropanol solvent which is preferred can be
substituted by other suitable hydroxylic solvents such as a combination of
anhydrous isopropanol with anhydrous ethanol or anhydrous methanol,
anhydrous n-butanol, anhydrous propanol or anhydrous isobutanol and the
like, with or without an anti-solvent (for example ethyl acetate) provided
the hydroxylic solvent solubilizes each of Ranitidine Free Base and
anhydrous hydrogen chloride gas and precipitates the desired form of Form
1 Ranitidine. Hydrochloride preferably slowly and uniformly. Anhydrous
n-butanol or anhydrous isobutanol with or without anhydrous isopropanol
can also be used. Persons skilled in the art given the above teachings
will perceive other suitable solvents (which may be an alkanol or
combination of alkanols at least one of which has 3-4 carbon atoms). The
solvent should once again be substantially anhydrous and may carry a small
amount of water for example less than about 2%, preferably less than about
1% and more preferably less than about 0.5%.
Thus, according to another aspect of the invention a new process for
consistently producing an improved form of Form 1 Ranitidine Hydrochloride
having improved filtration and drying characteristics is provided, the
said process comprising adding an anhydrous solution of anhydrous hydrogen
chloride gas in a substantially anhydrous hydroxylic solvent for example
including an alkanol having 3 or 4 carbon atoms, to an anhydrous solution
of Ranitidine Free Base in the same or different substantially anhydrous
hydroxylic solvent suitable for the purposes of the process (and
preferably including the same alkanol having 3 or 4 carbon atoms) and
preferably containing seeds of Form 1 Ranitidine Hydrochloride preferably
at temperatures in the order of 40.degree. C.-55.degree. C. and
subsequently recovering the improved form of Form 1 Ranitidine
Hydrochloride wherein the said substantially anhydrous solvent or solvents
has/have the characteristics that each solubilizes each of Ranitidine Free
Base and anhydrous hydrogen chloride gas and precipitates the desired form
of Form 1 Ranitidine Hydrochloride slowly and uniformly.
Where other salts of Ranitidine are in a form having unsatisfactory
filtration and drying characteristics, they may be converted to a suitable
form by the processes of this invention modified in such manner to produce
the desired salt and form consistent with this invention having
satisfactory filtration and drying characteristics. In this embodiment,
one skilled in the art would substitute the anhydrous hydrogen chloride by
a suitable anhydrous acid which would yield the desired salt.
For most consistency, the process is carried out in a temperature range of
between about 40.degree. C. and about 55.degree. C. when using
isopropanol. Persons skilled in the art will appreciate that the
temperature range is given as a guide and may vary with the choice of
solvent.
Where anhydrous isopropanol and ethanol are used as the solvent with an
anti-solvent ethyl acetate, the Ranitidine Free Base may be dissolved in
the isopropanol and ethanol combination and the hydrogen chloride gas may
be dissolved in the ethyl acetate and the solutions combined. Preferably
however a single solvent is used as it is more easily recovered and
recycled and preferably the solvent is isopropanol.
According to another aspect of the invention, an improved physical form of
Form 1 Ranitidine Hydrochloride is provided, the improved form of Form 1
Ranitidine Hydrochloride being hard dense crystals (thus being heavier and
more dense than previously known forms of Form 1 Ranitidine
Hydrochloride), providing improved drying characteristics and providing a
particle and crystal size which provides improved filtration
characteristics over the previous Form 1 Ranitidine Hydrochloride which
when produced in accordance with the teachings of Canadian Letters Patent
1,099,268 tended to retain more solvent during filtration, making drying
more difficult.
In this regard, the improved form of Form 1 Ranitidine Hydrochloride now
has characteristics of being harder and denser, and providing larger sized
crystals. The following characteristics are typical of the recovered Form
1 Ranitidine Hydrochloride:
Bulk Density not less than about 0.23 gm/ml
Tap Density not less than about 0.28 gm/ml
Melting Point same as Form 1
Infrared Spectrum same as Form 1
Raman Spectrum same as Form 1
The fact that the Tap and Bulk Densities are relatively close to one
another, indicates that the product produced is relatively hard and
therefore will retain very little solvent as opposed to a previous form of
Form 1 Ranitidine Hydrochloride (produced under Canadian Letters Patent
1,099,268), which was considered to be light and fluffy.
Because of the preferred methods of manufacture, the improved form of Form
1 of Ranitidine Hydrochloride is purer with a lesser number of impurities
incorporated into the crystalline structure. Infrared Spectrum analysis
was conducted on the samples and the resultant spectrum was consistent
with the published data in respect of Form 1 Ranitidine Hydrochloride. The
Infrared Spectrum Pattern was not consistent with the corresponding
published data on Form 2 Ranitidine Hydrochloride. Raman Spectroscopy was
performed which confirmed the production of Form I Ranitidine
Hydrochloride.
Form 2 Ranitidine Hydrochloride may be converted to Form 1 Ranitidine
Hydrochloride by the above methods. In this regard for example the Form 2
Ranitidine Hydrochloride may be dissolved in anhydrous methanol and
heated. Anhydrous isopropanol alcohol warmed to 45.degree. C. is added and
the solution is seeded with Form 1 Ranitidine Hydrochloride. On cooling
Form 1 Ranitidine Hydrochloride crystals can be recovered.
The following examples are offered as examples of the invention and are not
to be interpreted as limiting the scope of the invention.
EXAMPLE 1
Ranitidine Hydrochloride (Form #1)
Preparation in Isopropyl Alcohol from Ranitidine Base
Ranitidine base (31.44 g, 0.1 mol) was dissolved in anhydrous isopropyl
alcohol (isopropanol) (160 mL) by warming to 30.degree. C., filtering
through celite and washing the cake with anhydrous isopropyl alcohol (68
mL). The solution was warmed to 43.degree. C., seeds (Form #1, 0.2g) were
added and anhydrous hydrogen chloride in anhydrous isopropyl alcohol
(15.19 g, 24%, 1 equivalent) was added all at once. The temperature rose
to 51.degree. C. and the temperature was maintained at
45.degree.-50.degree. C. for 5 hours while the product crystallized. The
mixture was allowed to cool to 25.degree. C. The precipitate was filtered
and washed with anhydrous isopropyl alcohol (2.times.30 mL) to yield damp
Ranitidine Hydrochloride. Vacuum drying at 40.degree. C. overnight yields
34.26 g (0.0977 mol, 97.7%) of pure Ranitidine Hydrochloride (Form #1).
The I.R. in KBr of the crystals conformed to Form #1.
EXAMPLE 2
Ranitidine Hydrochloride (Form #1)
Conversion of Form #2 to Form #1
Ranitidine Hydrochloride Form #2 (5.0g) was dissolved in anhydrous methanol
(15 mL) warmed to 50.degree. C. To this solution of methanol anhydrous
isopropyl alcohol (19 mL) warmed to 45.degree. C. and Form #1 seeds (0.1
g) were added simultaneously over a period of 5 minutes. After 30 minutes,
another portion of anhydrous isopropyl alcohol (18 mL) was added. The
mixture was stirred at 50.degree. C. for 4 hours, cooled, filtered, and
washed with isopropyl alcohol (15 mL). The isopropyl alcohol damp crystals
were vacuum dried at 40.degree. C. overnight to yield 3.78 g (75.6%) of
Ranitidine Hydrochloride Form #1. The I.R. spectrum showed that the
crystals conformed to Form #1.
As many changes can be made to the preferred embodiments of the invention
without departing from the scope of the invention; it is intended that all
material contained herein be interpreted as illustrative of the invention
and not in a limiting sense.
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